On the Necessity of Ethical Guidelines for Novel Neurotechnologies.

Because novel neurotechnologies may alter human identity and society in profound ways, we advocate for the early integration of ethics into neurotechnology. We recommend developing and adopting a set of guidelines, like the Belmont Report on human subject research, as a framework for development and use of brain-related technologies.

Incorporating ethics and welfare into randomized experiments.

Randomized controlled trials (RCTs) enroll hundreds of millions of subjects and involve many human lives. To improve subjects' welfare, I propose a design of RCTs that I call Experiment-as-Market (EXAM). EXAM produces a welfare-maximizing allocation of treatment-assignment probabilities, is almost incentive-compatible for preference elicitation, and unbiasedly estimates any causal effect estimable with standard RCTs. I quantify these properties by applying EXAM to a water-cleaning experiment in Kenya. In this empirical setting, compared to standard RCTs, EXAM improves subjects' predicted well-being while reaching similar treatment-effect estimates with similar precision.

A comparative ethical analysis of the Egyptian clinical research law.

BACKGROUND: In this study, we examined the ethical implications of Egypt's new clinical trial law, employing the ethical framework proposed by Emanuel et al. and comparing it to various national and supranational laws. This analysis is crucial as Egypt, considered a high-growth pharmaceutical market, has become an attractive location for clinical trials, offering insights into the ethical implementation of bioethical regulations in a large population country with a robust healthcare infrastructure and predominantly treatment-naïve patients. METHODS: We conducted a comparative analysis of Egyptian law with regulations from Sweden and France, including the EU Clinical Trials Regulation, considering ethical human subject research criteria, and used a directed approach to qualitative content analysis to examine the laws and regulations. This study involved extensive peer scrutiny, frequent debriefing sessions, and collaboration with legal experts with relevant international legal expertise to ensure rigorous analysis and interpretation of the laws. RESULTS: On the rating of the seven different principles (social and scientific values, scientific validity, fair selection of participants, risk-benefit ratio, independent review, informed consent and respect for participants) Egypt, France, and EU regulations had comparable scores. Specific principles (Social Value, Scientific Value, and Fair selection of participants) were challenging to directly identify due to certain regulations embodying 'implicit' principles more than explicitly stated ones. CONCLUSION: The analysis underscores Egypt's alignment with internationally recognized ethical principles, as outlined by Emanuel et al., through its comparison with French, Swedish, and EU regulations, emphasizing the critical need for Egypt to continuously refine its ethical regulations to safeguard participant protection and research integrity. Key issues identified include the necessity to clarify and standardize the concept of social value in research, alongside concerns regarding the expertise and impartiality of ethical review boards, pointing towards a broader agenda for enhancing research ethics in Egypt and beyond.

Indignity of Nazi data: reflections on the utilization of illicit research.

Human rights may feel self-apparent to us, but less than 80 years ago, one of the most advanced countries at the time acted based on an utterly contrary ideology. The view of social Darwinism that abandoned the idea of the intrinsic value of human lives instead argued that oppression of the inferior is not only inevitable but desirable. One of the many catastrophic outcomes is the medical data obtained from inhuman experiments at concentration camps. Ethical uncertainty over whether the resulting insights should be a part of the medical literature provides a chance to consider the seemingly irreplaceable social construct of human dignity. Would any medical benefit justify the utilization of this illicit data? Would utilization even qualify as an insult to the dignity of the exploited subjects, or is this a question about intersubjective meaning? This work discusses the wisdom in blind adherence to human dignity, the possibility of retrospective insults, moral complicity, contrary viewpoints, and possible resolutions.

Ethicizing history. Bioethical representations of Nazi medicine.

The article presents and analyzes different approaches of U.S. bioethicists in comprehending the Nazi medical crimes after 1945. The account is divided into two sections: one dealing with discussions on research ethics and the Nuremberg Code up until the 1970s and the other ranging from the 1970s to the present and highlighting bioethics' engagement with Nazi analogies. The portrayal of different bioethical scholars, institutions, and documents-most notably Henry K. Beecher, Jay Katz, the Belmont Report, the Hastings Center, Arthur L. Caplan, and Robert M. Veatch-provides a nuanced interpretation of the motives that bioethicists held and the strategies that they applied to establish an understanding of the Nazi medical crimes and their relation to contemporary bioethical issues. In this, the different approaches shared a common goal: To integrate the Nazi medical crimes into an ethical framework by means of selective acknowledgments and representation of their history.

Ethics in field experimentation: A call to establish new standards to protect the public from unwanted manipulation and real harms.

In 1966, Henry Beecher published his foundational paper "Ethics and Clinical Research," bringing to light unethical experiments that were routinely being conducted by leading universities and government agencies. A common theme was the lack of voluntary consent. Research regulations surrounding laboratory experiments flourished after his work. More than half a century later, we seek to follow in his footsteps and identify a new domain of risk to the public: certain types of field experiments. The nature of experimental research has changed greatly since the Belmont Report. Due in part to technological advances including social media, experimenters now target and affect whole societies, releasing interventions into a living public, often without sufficient review or controls. A large number of social science field experiments do not reflect compliance with current ethical and legal requirements that govern research with human participants. Real-world interventions are being conducted without consent or notice to the public they affect. Follow-ups and debriefing are routinely not being undertaken with the populations that experimenters injure. Importantly, even when ethical research guidelines are followed, researchers are following principles developed for experiments in controlled settings, with little assessment or protection for the wider societies within which individuals are embedded. We strive to improve the ethics of future work by advocating the creation of new norms, illustrating classes of field experiments where scholars do not appear to have recognized the ways such research circumvents ethical standards by putting people, including those outside the manipulated group, into harm's way.

"The Warmth of His Continuing Interest": Henry K. Beecher, the Bioethics Revolution, and Pharmaceutical Industry Funding of Academic Medical Science in Cold War America.

This paper examines anesthesiologist Henry K. Beecher's funding relationship with pharmaceutical manufacturer Edward Mallinckrodt, Jr. Beecher is a familiar figure to both medical ethicists and historians of medicine for his role in the bioethics revolution of the 1960s and 1970s. In particular, his 1966 article "Ethics and Clinical Research" is widely considered a turning point in the post-World War II debate about informed consent. We argue that Beecher's scientific interests should be understood in the context of his funding relationship with Mallinckrodt and that this relationship shaped the direction of his work in important ways. We also argue that Beecher's views on research ethics reflected his assumption that collaboration with industry was a normal part of how academic science is conducted. In the conclusion of the paper we suggest that Beecher's failure to consider his relationship with Mallinckrodt as worthy of ethical deliberation has important lessons for academic researchers who collaborate with industry today.

[Current status and challenges of long-term safety evaluation of using tests of cosmetics on human body].

The use of cosmetics in the crowd has the long-term characteristics. The adverse reactions of cosmetics reported in other country in the world suggest that human patch tests and short-term human using test may not be sufficient to evaluate the safety of high-risk new cosmetic raw ingredients, and long-term human using test should be conducted for evaluation. Therefore, this article reviews the key factors that affect long-term human trial trials, such as site of use, single-use amount, frequency of use, duration of use, and subject conditions, providing supportive evidence for standardized safety evaluation standards for long-term human using test of cosmetics.

The Dangers of White Supremacy: Nazi Sterilization and Its Mixed-Race Adolescent Victims.

Mixed-race African German and Vietnamese German children were born around 1921, when troops drawn from the French colonial empire occupied the Rhineland. These children were forcibly sterilized in 1937. Racial anthropologists had denounced them as "Rhineland Bastards," collected details on them, and persuaded the Nazi public health authorities to sterilize 385 of them. One of the adolescents later gave public interviews about his experiences. Apart from Hans Hauck, very few are known by name, and little is known about how their sterilization affected their lives. None of the 385 received compensation from the German state, either as victims of coerced sterilization or as victims of Nazi medical research. The concerned human geneticists went unprosecuted. (Am J Public Health. 2022;112(2):248-254. https://doi.org/10.2105/AJPH.2021.306593).

A Scientific Method to the Madness of Unit 731's Human Experimentation and Biological Warfare Program.

The Japanese Imperial Army Unit 731's Biological Warfare (BW) research program committed atrocious crimes against humanity in their pursuit of biological weapons development during the Second World War. Due to an American cover-up, the details behind Unit 731's human experimentation were slow to be revealed. The recent literature discloses the gruesome details of the experiments but characterizes the human trials as crude in nature. Further, there is a lack of clarity as to how human trial results were extrapolated for use in real world missions. Through an examination of testimony from the Soviet Union's Khabarovsk War Crime Trials, this paper argues that Unit 731's inoculation and airborne warfare experiments on prisoners of war were scientifically rigorous. The scientific method is used as the basis against which the scientific rigor of the experiments is tested. The paper reveals that the successes and failures of the human trials were extrapolated to BW missions during the Sino-Japanese war. American researchers' expectations of BW data were fulfilled, thus paving the way for an immunity deal. Ethical standards in medicine before WWII were not well established, but wartime medical practices and experimentation reveal the context in which the pursuit of scientific knowledge has no boundaries.

Less severe clinical symptoms of Norwalk virus 8fIIb inoculum compared to its precursor 8fIIa from human challenge studies.

Noroviruses (NoV) are a leading cause of epidemic gastroenteritis. Human challenge studies have been used to examine the infectivity, pathogenicity, and host immune response to NoV as well as vaccine efficacy. The goal of this study was to conduct a meta-analysis of data from five previously completed human challenge trials and compare the response to the secondary NV inoculum (8fIIb) to its precursor (8fIIa). We investigated a total of 158 subjects: 76 subjects were experimentally challenged with NV inoculum 8fIIa, and 82 subjects were challenged with 8fIIb. We compared demographic characteristics, infection, illness, mean severity score, blood types, and duration of viral shedding between the two groups of subjects. There were no statistically significant differences in overall infection and illness rates between subjects inoculated with 8fIIa and 8fIIb. However, individuals challenged with 8fIIa had significantly higher severity scores (5.05 vs. 3.22, p = .008) compared with those challenged with 8fIIb. We also observed that infection with 8fIIb was associated with significantly longer duration of viral shedding compared with 8fIIa (11.0 days vs. 5.0 days, p = .0005). These results have serious implications for the development of new NoV inocula for human challenge studies to test candidate vaccine efficacy-where illness severity and duration of viral shedding are important outcomes.

Performance of BioFire array or QuickVue influenza A + B test versus a validation qPCR assay for detection of influenza A during a volunteer A/California/2009/H1N1 challenge study.

BACKGROUND: Influenza places a significant burden on global health and economics. Individual case management and public health efforts to mitigate the spread of influenza are both strongly impacted by our ability to accurately and efficiently detect influenza viruses in clinical samples. Therefore, it is important to understand the performance characteristics of available assays to detect influenza in a variety of settings. We provide the first report of relative performance between two products marketed to streamline detection of influenza virus in the context of a highly controlled volunteer influenza challenge study. METHODS: Nasopharyngeal swab samples were collected during a controlled A/California/2009/H1N1 influenza challenge study and analyzed for detection of virus shedding using a validated qRT-PCR (qPCR) assay, a sample-to-answer qRT-PCR device (BioMerieux BioFire FilmArray RP), and an immunoassay based rapid test kit (Quidel QuickVue Influenza A + B Test). RESULTS: Relative to qPCR, the sensitivity and specificity of the BioFire assay was 72.1% [63.7-79.5%, 95% confidence interval (CI)] and 93.5% (89.3-96.4%, 95% CI) respectively. For the QuickVue rapid test the sensitivity was 8.5% (4.8-13.7%, 95% CI) and specificity was 99.2% (95.6-100%, 95% CI). CONCLUSION: Relative to qPCR, the BioFire assay had superior performance compared to rapid test in the context of a controlled influenza challenge study.

Building global capacity for brain and nervous system disorders research.

The global burden of neurological, neuropsychiatric, substance-use and neurodevelopmental disorders in low- and middle-income countries is worsened, not only by the lack of targeted research funding, but also by the lack of relevant in-country research capacity. Such capacity, from the individual to the national level, is necessary to address the problems within a local context. As for many health issues in these countries, the ability to address this burden requires development of research infrastructure and a trained cadre of clinicians and scientists who can ask the right questions, and conduct, manage, apply and disseminate research for practice and policy. This Review describes some of the evolving issues, knowledge and programmes focused on building research capacity in low- and middle-income countries in general and for brain and nervous system disorders in particular.

Stakeholder Perspectives on Engaging With Cerebral Palsy Research Studies After Onset of COVID-19 in the United States.

OBJECTIVE: To investigate the effect of the coronavirus disease 2019 (COVID-19) pandemic on perspectives toward participation in cerebral palsy (CP) research. DESIGN: An online survey with questions relating to the comfort levels of research participation was filled out by people who had CP or had a child with CP. SETTING: The online survey was administered through Research Electronic Data Capture platform. PARTICIPANTS: A total of 233 (n=233) individuals with CP (42.5%; n=99) or with a child with CP (57.1%; n=133) consented and at least partially completed the online survey (n=210 complete; n=23 partially complete). All participants resided in the United States. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Readiness to participate was analyzed in the context of the time point for research participation during COVID-19 and whether or not the study offered direct benefits to participants. RESULTS: Participants were consistently willing to participate sooner in studies that offered direct benefit than in those that did not. Adults responding for themselves had sooner time points for studies without direct benefit compared with parents answering for a child (P=.030). Gross Motor Function Classification System level, but not age or CP type, affected the time point for studies without direct benefit (P=.017). Personal values influenced selected time point for studies without direct benefit (P=.007), whereas environmental factors affected the time point for studies with direct benefit (P=.002). Local COVID-19 incidence rates were not associated with time points for either research type; however, respondents expected precautions to be taken if they chose to participate. CONCLUSIONS: As the pandemic evolves, researchers should consider the perspectives of potential participants as well as ethical and safety factors when reinitiating in-person CP research.

Controlled Human Infection Studies: Proposals for guidance on how to design, develop and produce a challenge strain.

There is an increasing need to establish quality principles for designing, developing and manufacturing challenge agents as currently these agents are classified differently by various jurisdictions. Indeed, considerations for challenge agent manufacturing vary between countries due to differences in regulatory oversight, the categorization of the challenge agent and incorporation into medicinal/vaccine development processes. To this end, a whitepaper on the guidance has been produced and disseminated for consultation to researchers, regulatory experts and regulatory or advisory bodies. This document is intended to discuss fundamental principles of selection, characterization, manufacture, quality control and storage of challenge agents for international reference. In the development phase, CMC documentation is needed for a candidate challenge agent, while standard operating procedure documentation is needed to monitor and control the manufacturing process, followed by use of qualified methods to test critical steps in the manufacturing process, or the final product itself. These activities are complementary: GMP rules, which intervene only at the time of the routine manufacturing of batches, do not contribute to the proper development and qualification of the candidate product. Some considerations regarding suitability of premises for challenge manufacturing was discussed in the presentation dedicated to "routine manufacturing".

Clinical experience with isavuconazole in healthy volunteers and patients with invasive aspergillosis in China, and the results from an exposure-response analysis.

BACKGROUND: Isavuconazole is a broad-spectrum triazole for the treatment of invasive fungal disease (IFD). OBJECTIVE: To investigate the clinical experience with isavuconazole in Chinese individuals. PATIENTS/METHODS: Participants were Chinese healthy volunteers from a Phase I pharmacokinetics (PK) and safety study of single/multiple doses of isavuconazole (n = 36) and Chinese patients from the global Phase III SECURE study that assessed safety and efficacy of isavuconazole vs voriconazole for IFD treatment (n = 26). RESULTS: No clinically relevant differences in PK were found between Chinese and Western participants, although exposure was increased in Chinese volunteers. Treatment-emergent adverse events (TEAEs) were reported in 75.0% of healthy volunteers, many of which were infusion-related. No serious AEs were reported. In SECURE, findings in Chinese patients (n = 26) were similar to the global population. For patients who received ≥1 dose of study drug, allcause mortality from first dose to Day 42 was 10.0% (1/10) with isavuconazole and 25.0% (4/16) with voriconazole (treatment difference [95% confidence interval, CI]: -15.0% [-43.2%, 13.2%]). Overall response at the end of treatment for patients with proven/probable IFD was 25.0% and 16.7% with isavuconazole and voriconazole, respectively (treatment difference [95% CI] -8.3% [-60.2%, 43.5%]). Isavuconazole was associated with lower incidence of hepatobiliary, eye, skin, subcutaneous tissue and psychiatric disorders compared with voriconazole and lower incidence of treatment-related TEAEs, serious TEAES or death overall. CONCLUSIONS: Although further research is required, this study demonstrated a favourable risk-benefit profile of isavuconazole in Chinese patients.

Institutional Review Board Quality, Private Equity, and Promoting Ethical Human Subjects Research.

Evaluating the quality and effectiveness of the institutional review boards (IRBs) responsible for overseeing research involving human participants is critically important but perpetually challenging. Seemingly common-sense measures, such as the number of proposals approved with and without major modifications and the number of unexpected adverse events occurring in approved protocols, can be misleading indicators of participant protection, and regulatory compliance may not correspond to achieving ethical goals. These measurement challenges make it difficult to assess the validity of concerns about different IRB models. A group of U.S. senators recently raised questions about the increasing use of for-profit IRBs to review research proposals (as opposed to boards typically housed at academic medical centers and health care institutions) and, more specifically, about the growing trend of private equity ownership and consolidation of for-profit IRBs. Although all IRBs face pressure to speed reviews and none are entirely free of conflicts of interest, the private equity model is particularly susceptible to approaches that could undercut the ethical mission of IRBs to protect and promote the rights and welfare of research participants. Ideally, the quality of board oversight could be measured directly, rather than relying on the heuristic of board type; this article describes several current efforts toward this goal. In the meantime, one improvement may be to pursue a new model of IRB oversight: independent nonprofit boards that stand apart from research institutions, take advantage of business approaches to research review, and minimize conflicts of interest.